Postoperative jaundice is a frequently (up to 14%) encountered phenomenon of unknown etiology. This study aims at elucidating potential mechanisms contributing to the development of benign postoperative jaundice. We hypothesize that increased turnover hepatic heme and heme proteins is the main pathogenetic mechanism. We therefore propose to study the effect of different conditions, often associated with the postoperative patient, on heme turnover and to probe the biologic sequelae of demonstrated alterations in hepatic heme turnover. The following conditions, often encountered in the postoperative patient, will be studied: a) intrahepatic cholestasis (induced by ethinyl estradiol, phalloidin, endotoxin and taurolithocholate); b) total parenteral hyperalimentation (effects of glucose, lipid emulsions, amino acid hydrolysates and any combination thereof); c) different forms of anesthesia (inhalation anesthetics and barbiturates) and d) effects of hypoxemia and of hypovolemia. Hepatic heme and hemoprotein turnover will be studied by means of a newly developed 14-CO breath test in unstressed rats. The animals will be infused continuously with 5-14C-delta-aminolevulinic acid (ALA); this is incorporated into heme and upon degradation yields 14-CO and biliverdin in a stoichiometric relationship. This model has the advantage of being able to detect minor changes in hepatic heme turnover in virtually unstressed animals. Since it will not detect increased heme turnover depending on pathways not involving formation of CO, incorporation of ALA into hepatic heme will be directly assayed by single and double pulse-labelling experiments. The activity of the rate-limiting enzymes in heme synthesis and degradation, ALA synthetase and heme oxygenase will be quantitated in the appropriate subcellular fractions under the different experimental conditions. The biological sequelae of increased heme/heme protein turnover will be probed by a) measuring the hepatic microsomal content of cytochrome P-450, the major hepatic heme protein; b) by probing specific functions of cytochrome P-450 namely the hydroxylation of hydroxylation of antipyrine and propranolol, and c) by determining the pharacokinetic fate of a high- and a low-extraction compound, propranolol and anti-pyrine, in vivo. These studies will improve our understanding of the regulation of heme metabolism in common clinical situations and will permit predictions about the handling of xenobiotics under these circumstances.